heamatological condition under anaemias

1. Megaloblastic Anaemia

2. Introduction
 This is a group of aneamia in which the erythroblasts in
the bone marrow and RBC in the peripheral blood are
large.
 Show a characteristic abnormality-
Maturation of the nucleus being delayed relative to that
of the cytoplasm.
The nuclear chromatin maintains an open, stipled,lacy
appearance despite normal Hb formation in the
cytoplasm of erythroblasts as they mature.

3. Introduction
 In megaloblastic anaemia, the granulocytic and
megakaryocytic maturation are also affected and this
leads to pancytopenia
 There are two principal causes of megaloblastic anemia
 Folate deficiency
 Vitamin B12 deficiency
 Both vitamins are critical for DNA synthesis
 Megaloblastic dyspoiesis (abnormal synthesis) occurs
when the DNA synthesis in the hematopoietic system is
disrupted or slowed down.

4.  Other rapidly proliferating cells in the body are also affected.
 Administration of drugs that interfere with DNA
metabolism can be the cause of a megaloblastic anemia.
 On rare occasions there is an inherited disorder that affects
DNA synthesis
 Primary defect in DNA replication is usually due to depletion
of deoxythymidine triphosphate(dTTP) which leads to
retarded mitosis, and therefore retarded nuclear maturation.
 The depletion of dTTP is usually due to a deficiency of
vitamin B12 or folic acid.

5. Vitamin B12
 Synthesized in nature by microorganisms
 Animals acquire it by eating other animal foods.
 The vitamin consists of a small group of compounds the
cobalamins.
 Contains cobalt atom at the centre of a corrin ring which
is attached to a nucleotide portion.
 Found in foods of animal origin such as liver, meat, fish
etc.
 Does not occur in fruits, cereals or vegetables.

6. Absorption
 Humans need 3-5 ug of vitamin B12 per day.
 Since 70% of dietary B12 is absorbed, the diet needs to
contain 5-7 ug/day.
 Normal diet contains excess ofVB12 compared with
daily needs.
 B12 is combined with intrisic factor which is
synthesized by the gastric parietal cells.
 The IF- B12 complex then bind to a specific receptor-
cubilin in the distal ileum where B12 is absorbed

7. Absorption
 When B12 is released from the mucosal cell, it binds to
transport proteins in the bloodstream (transcobalamine
II).
 A congenital deficiency in type II can lead to a
megaloblastic anemia.
 B12 is transported to the bone marrow for use or to the
liver for storage

8. Causes of Vitamin B12 deficiency
 Inadequate intake of external factor (vitamin B12)
 Disruption of absorption of vitamin B12 because of
invasion by fish worm.This worm is able to absorb large
amounts of vitamin B12.
 Malabsorption: when there is something wrong with
intrinsic factor
 Disturbed metabolism
 Age from 50-55 years of age, vitamin B12 is harder to
absorb hence vitamin B12 supplements are important
after this stage.

9. Causes of Vitamin B12 deficiency
 Chronic alcoholism
 Liver damage by hepatitis (liver is the major store of
vitamin B12)

10. Folic Acid(Pteroyl glutamic)
 Is found in most foods, including eggs, milk, yeast, and
liver.
 Is abundant in green, leafy vegetables and is synthesized
by many microorganisms.
 Is destroyed by heat
 Humans are unable to synthesize the folate structure
and thus require preformed folate

11. Absorption,transport and function
 Dietary folates are converted to methyl tetrahydrofolate
during absorption through the upper small intestine .
 Once inside the cell they are converted to
polyglutamates.
 Humans need to get about 50 ug/day of folic acid from
the diet
 Folates are needed in a variety of biochemical reactions
eg in the conversion of homocystein to Methionine.

12. Causes of Folic acid deficiency
 Inadequate diet is the major cause –occurs most often in
the poor, elderly, alcoholics.
 Malabsorption can be caused by tropical sprue, a large
worm which absorbs folate
 Excess utilization which can be physiological (normal) or
pathological

13. Causes of Folic acid deficiency
 Physiological conditions:
 Pregnancy and lactation period
 Prematurity
 Growth in children
 Pathological conditions:
 Haematologic diseases such as haemolytic anemia with increased
destruction of RBC’s
 Different types of malignancies e.g. carcinoma, lymphoma
 Inflammatory conditions e.g.TB, rheumatoid arthritis and
dermatitis, as
 Systemic infections such as malaria.

14. Causes of Folic acid deficiency
 Increased loss such as in patients undergoing
hemodialysis
 Drug inhibition – examples are oral contraceptives,
anticoagulant drugs, alcohol, and isoniazid

15. Pathogenesis of Megaloblastic
anaemia
 The morphologic hallmark of megaloblastic anemia is the
presence of megaloblasts, enlarged erythroid precursors
that give rise to abnormally large red cells (macrocytes).
 Granulocyte precursors are also increased in size.
 Underlying this cellular gigantism is a defect in DNA
synthesis that impairs nuclear maturation and cell
division.
 Because the synthesis of RNA and cytoplasmic elements
proceeds at a normal rate and thus outpaces that of the
nucleus, the hematopoietic precursors show nuclear-
cytoplasmic asynchrony.

16. Pathogenesis of Megaloblastic
anaemia
 This maturational derangement contributes to the
anemia in several ways.
 Many megaloblasts are so defective in DNA synthesis
that they undergo apoptosis in the marrow (ineffective
hematopoiesis).
 Others mature into red cells but do so after fewer cell
divisions, further diminishing the output of red cells.

17. Pathogenesis of Megaloblastic
anaemia
 Granulocyte and platelet precursors are also affected
(although not as severely) and most patients present with
pancytopenia (anemia, thrombocytopenia, and
graulocytopenia).

20. Clinical features of Vitamin B
deficiency
 Fatigue, weakness, palpitations during physical exertion.
These are general for all types of anemia
 Glossitis: patients have “polished tongue” beefy red
tongue with burning sensations which are very painful
 Small increase of spleen size
 May be mildly jaundiced from excess breakdown of Hb
due to increase in defective erythropoiesis

21. Clinical features of Vitamin B
deficiency
 Mild symptoms of malabsorption with loss of weight of
patients
 Patients may have purpura due to thrombocytopenia
(deficiency of platelets)
 Hyperpigmentation or hypopigmentation of the skin
usually seen on soles and palms of patients and less
frequently across small joints of hands and feet.
 Severe cases of B12 deficiency can cause progressive
neural fatigue with loss of sensation of hands, legs and
feet.

22.  This neuropathy is symmetrical and affects lower limbs
more than upper limbs, males more than females.
 Patients may feel tingling in the feet and have difficulties
walking, may even fall due to loss of muscle control
 Optic atrophy in long standing severe cases causes
yellow-blue color blindness of patients, it is quite rare
and due to severe B12 deficiency
 Sterility

24. Laboratory findings
 Macrocytosis: Erythrocytes are larger in size and are usually
oval in shape
 Low Hb count
 Low reticulocyte count
 Thrombocytopenia
 Hypersegmented neutrophils with more than 5 lobes
 Howell-jelly bodies are also seen
 Low leukocyte count
 Normochromic

25. Laboratory findings
 The bone marrow is hypercellular and you can see;
Megaloblasts
 Large erythroblasts, many dying erythroblasts
Abnormally shaped metamyelocytes large in size

26. Clinical features of Folic acid deficiency
 Quite similar to vitamin B12 deficiency but no
neurological problems;
 Increased susceptibility to different infections due to
neutropenia, may develop immune deficiency
 Long standing cases may cause hyperpigmentation of skin
 Do not develop neuropathy
 Features are weaker in folic acid deficiency than in
vitamin B12 deficiency

27. Blood picture
 Macrocytosis: large oval erythrocytes especially in long
standing cases
 Poikilocytosis and Anisocytosis
 Hypersegmented neutrophils
 Howell-jelly bodies
 ReducedWBC count and low reticulocyte count
 Reticulocyte count is low
 Bone marrow is hyper cellular and you can see a lot of
megaloblasts in the bone marrow

28. Treatment
 Most cases only need therapy with the appropriate
vitamin.
 If large doses of folic acid (e.g.5 mg/day) are given in B
12 deficiency they cause a haematological response but
may aggravate the neuropathy.
 They should therefore not be given alone unless B12
deficiency has been excluded.


29. Treatment
 In severely anaemic patients who need treatment
urgently it may be safer to initiate treatment with both
vitamins after blood has been taken for B 12 and folate
estimation and a bone marrow test has been performed.
 In the elderly, the presence of heart failure should be
corrected with diuretics.
 Blood transfusion should be avoided if possible as it may
cause circulatory overload.

30. Treatment